Department of Internal Medicine

Michael Grever, MD, Chair

The Department of Internal Medicine comprises 12 divisions, each dedicated to innovations in research, education and patient care. Following are Division descriptions and research highlights for 2007.

Division of Cardiovascular Medicine
William Abraham, MD, Director
With nearly 70 full-time clinical and research faculty, Cardiovascular Medicine has many programs in basic, translational and clinical research. Collaborative basic research is performed in Ohio State’s Davis Heart and Lung Research Institute (DHLRI). The primary vehicle for patientoriented research is the Cardiovascular Clinical and Translational Research Organization (CCTRO), formerly called the Cardiovascular Clinical Research Unit. In partnership with researchers, healthcare professionals and patients, the CCTRO conducts clinical trials on new cardiovascular drug-and-device therapies. By linking Ohio State’s Richard M. Ross Heart Hospital and DHLRI, the CCTRO brings clinical and basic researchers together to improve patient care and outcomes. The CCTRO, with 28 research staff members, manages more than 100 clinical research projects, including investigator-initiated single-site studies, National Institutes of Health (NIH)- sponsored multisite trials, and industry-sponsored trials. Studies focus on heart failure, interventional cardiology, sleep disorders, electrophysiology, non-invasive imaging, exercise/ prevention, vascular biology, cardiac genotyping and pulmonary hypertension. Study results form the basis for standard-of-care
practices.

Ongoing Research Programs

Ayesha Hasan, MD, is principal investigator (PI) for a study titled “CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart
Failure Patients. (CHAMPION).” (CardioMEMS, Inc.)
John Hummel, MD, is PI for a study titled “Catheter Ablation vs. Antiarrhythmic Drug Therapy (CABANNA).” (Duke University/NIH)
Rami Khayat, MD, and William Abraham, MD, are PIs for a study called “The Role of Diagnosis and Treatment of Sleep Apnea in the Acute Exacerbation of Heart Failure.”
(Respironics, Inc.)
Subha Raman, MD, is PI for a study titled “Reduction of Infarct Expansion and Ventricular Remodeling with Erythropoietin After Acute MI (REVEAL).” (Duke/NIH)
The KATP project led by Rich Gumina, MD, is the focus of grants submitted to the American Heart Association and the NIH. This research seeks to understand: how the level of the KATP channel, influenced by sex and age, alters the susceptibility of the myocardium to ischemic injury; how the KATP channel regulates calcium and is influenced by the K channel; and how to develop mechanisms to deliver cardiovascular protective molecules to sites of injury.
Sanjay Rajagopalan, MD, and colleagues are studying angiogenesis using novel platform-based strategies and developing approaches for the diagnosis and treatment of atherosclerosis. Much of this research focuses on identifying proinflammatory pathways that are stimulated by environmental factors and on imaging approaches to allow tracking of inflammatory cell trafficking in tissue niches. The laboratory is funded by two NIH grants.
The thrust of research by Periannan Kuppusamy, PhD, is on imaging, focusing on new probes and procedures for highresolution imaging of free radicals and oxygen in cardiovascular disease. His lab, funded by four NIH R01 grants, also is developing multifunctional drugs for cardiac diseases, including ischemia-reperfusion injury, restenosis, arrhythmia and cardiac hypertrophy. Based on his more than a decadelong
work and collaboration, Kuppusamy was awarded the title “Doctor Honoris Causa” by the University of Pécs, in Pécs, Hungary.
A major section of the research group led by Jay Zweier, MD, is mechanisms of postischemic heart damage and ischemiareperfusion injury. By understanding the role of free radicals and other mediators of postischemic injury, scientists intend to develop approaches to maximize myocardial salvage in the setting of acute myocardial infarction and other ischemic syndromes. The Zweier group is also developing magnetic resonance techniques and instrumentation for detecting and measuring cardiovascular disease and determining the role of free radicals in disease pathophysiology; novel electron paramagnetic resonance (EPR) and nuclear magnetic resonance (NMR) instrumentation is being developed for this work.
Cardiovascular Medicine and the CCTRO led investigations of the efficacy and safety of hemodynamic monitoring devices for improving treatment outcomes of patients with heart failure. In 2007, Ohio State scientists participated in clinical trials for the HeartPod (Savacor, Inc.), Wireless Pressure Sensor (CardioMEMS, Inc.), and Chronicle ICD (Medtronic, Inc.). OSUMC has participated in both the feasibility and pivotal studies of these novel technologies, highlighting collaboration between heart-failure specialists and electrophysiologists. Garrie Haas, MD, William Abraham, MD, and Ayesha Hasan, MD, are Ohio State PIs for these studies.
The OSU Sleep-Heart Program, a multidisciplinary clinical and research initiative for studying cardiovascular consequences of sleep disorders, is led by William Abraham, MD,
Phil Binkley, MD, and Garrie Haas, MD, from Cardiovascular Medicine, and Rami Khayat, MD, from the Division of Pulmonary, Allergy, Critical Care and Sleep Medicine. In 2007, researchers studied the prevalence and clinical outcomes of sleep apnea in patients with heart failure, sleep treatments for cardiac patients, and consequences of oxidative stress in sleep apnea.
2007 saw significant growth in studies for treating atrial fibrillation, including studies in ultrasound (ProRhythm), laser (Cardiofocus), cryo/freezing (CryoCath Technologies)
and radiofrequency (BioSense Webster). Another investigational treatment involves implanting a left atrial appendage closure device (Atritech, Inc) that allows patients to
discontinue the use of coumadin. PIs for these studies include Emile Daoud, MD, John Hummel, MD, and Steve Kalbfleisch, MD.
Studies on the KATP channel examined whether sex differences exist in the innate susceptibility of the myocardium to ischemic injury in relation to the sarcolemmal ATP-sensitive potassium (KATP) channel. Researchers found that the female heart devoid of the KATP channel exhibited markedly increased diastolic pressures and in vivo calcium loading in response to ischemia and metabolic stress. This work describes for the first time in vivo an increase in calcium loading in response to knockout of the KATP channel and shows that calcium loading and diastolic dysfunction was surprisingly worse in female hearts.
A paper by Sanjay Rajagopalan, MD, on the use of a constitutively active hypoxia-inducible factor-1alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients was the first phase I trial using an adenoviral gene transfer approach to induce angiogenesis with hypoxia inducible factor in peripheral arterial disease. The trial demonstrated safety and allowed assessment of limited efficacy, paving the way for a large phase II trial being conducted in the United States and Europe.
Periannan Kuppusamy, PhD, published two seminal papers that received national attention, one on the labeling of stem cells with oxygen-sensing nanoprobes and the other on the use of in vivo electron paramagnetic resonance technology to monitor tissue oxygenation in the infarct myocardium before and after treatment with transplanted stem cells. Using an animal model of a heart attack, the studies demonstrated noninvasive monitoring and follow-up of tissue oxygenation for weeks after cell therapy. The results showed a significant enhancement of oxygen to the heart at the site of cell transplantation when compared with non-treated controls.
Nitric oxide synthase (NOS) is an enzyme regulating vascular tone and flow; the postischemic heart loses vasodilatory function due to alterations in NOS. Jay Zweier, MD, and colleagues observed for the first time that the critical cofactor for the enzyme tetrahydrobiopterin (BH4) is depleted during myocardial ischemia, causing loss of production of the endothelial-derived relaxing factor nitric oxide. With BH4 administration in liposomal formulations, coronary vasodilation was restored, proving a promising approach to reversing endothelial dysfunction in the postischemic heart and in acute coronary syndromes in general.

Division of Dermatology
Mark Bechtel, MD, Director
Dermatology collaborates with the Division of Hematology and Oncology in clinical management, clinical trial and oncologic genetic research on cutaneous lymphoma and cutaneous oncology. Dermatology is also engaged in a cutaneous oncology focus group involving dermatology, dermatopathology, hematology/oncology, surgical oncology and cutaneous oncology researchers at OSUMC. A cutaneous lymphoma focus group was established to facilitate research, scholarship and management of this disease. A complex dermatology clinic enables medical students and residents to manage and evaluate patients with severe psoriasis, autoimmune blistering diseases and collagen vascular disease. A new Mohs micrographic and dermatologic surgical center opened at the Martha Morehouse Medical Plaza under the direction of David Lambert, MD. Matthew Zirwas, MD, directs the Ohio State Contact and Occupational Dermatitis Center and the new phototherapy unit and cutaneous laser clinic. Susan Massick, MD, has joined the Division as a clinical dermatologist, and Patti Witman, MD, as director of Pediatric Dermatology at Nationwide Children’s Hospital.

Ongoing Research Programs and Accomplishments of 2007

David Lambert, MD, is collaborating with Ronald Glaser, PhD, in a National Institutes of Health (NIH)-funded study on the effects of stress on basal cell carcinoma.
David Lambert, MD, also is collaborating with Amanda Tolland, PhD, of the Department of Molecular Virology, Immunology and Medical Genetics, to study the molecular genetics of squamous cell carcinoma.
A research program grant from the Dermatology Foundation supports promotion of cutaneous oncology at OSUMC and has increased collaboration between clinicians and bench researchers.
Mark Bechtel, MD, Patti Witman, MD, and Matthew Zirwas, MD, were recognized as Best Doctors in America for 2007-2008.
Mark Bechtel, MD, served on the American Academy of Dermatology’s Guidelines and Standards of Care Task Force.
Matthew Zirwas, MD, was elected to the Board of Directors of the American Contact Dermatitis Society.

Division of Endocrinology, Diabetes and Metabolism
Kwame Osei, MD, Director

Endocrinology, Diabetes and Metabolism excels in research, teaching and patient care. In coming years, the Division will strengthen and expand its accomplishments in specific and thematic areas through research in diabetes, islet cell transplantation, osteoporosis and bone diseases, thyroid cancer and benign thyroid-pituitary disorders.

Ongoing Research Programs

Thyroid Cancer Program at Martha Morehouse Medical Plaza
Human and Non–Human Primate Experimental Model of ICTP Diabetes Research Center
Women’s Health Initiative (WHI) and Osteoarthritis Initiative (OAI)

Research Accomplishments of 2007

In conjunction with The Ohio State University Comprehensive Cancer Center and Ohio State’s James Cancer Hospital and Solove Research Institute, the Division has established the Thyroid Cancer Program at the Martha Morehouse Medical Plaza. This program defines the molecular basis of thyroid cancer growth and metastasis, develops cancer chemotherapies as an adjunct for radioiodine and thyroxine therapy, and develops translational research programs in thyroid cancer. Recently, program member Matthew Ringel, MD, was awarded a National Cancer Institute program project grant for studying genetic and signaling pathways in epithelial thyroid cancer.
The Division, in conjunction with The Ohio State University Comprehensive Transplantation Center and Diabetes Research Center, received FDA approval to begin human islet cell transplantation. This will complement a study called “Whole Pancreas Transplantation and a Non-Human Primate Experimental Model of the Islet Cell Transplantation Progra (ICTP).” The objectives of the ICTP, led by investigators Kwame Osei, MD, and Elizabeth Diakoff, MD, are to develop therapies to ensure longstanding islet cell functional survival
in humans by immunoprotection, and to promote islet cell growth and anti-apoptosis.
The Division supports the NIH Center for Women’s Health Initiative (WHI). The OSU WHI Center is led by Rebecca Jackson, MD, and it has contributed to the understanding of major health issues related to middle-aged and elderly women.
The Division supports an NIH Clinical Center for the Osteoarthritis Initiative (OAI). One of four centers in the country, the OAI at Ohio State has contributed to the understanding of health issues related to osteoarthritis, exercise performance and quality of life in middle-aged and elderly patients. Rebecca Jackson, MD, is principal investigator.

Division of Gastroenterology, Hepatology and Nutrition
G. Nicholas Verne, MD, Director
Gastroenterology, Hepatology and Nutrition experienced a major expansion of faculty in 2007. G. Nicholas Verne, MD, is the new division director. He has an active National Institutes of Health (NIH)- and Veterans Administrationfunded research program that focuses on the neurobiology of functional bowel disorders in civilian and veteran patients. Tushar Patel, MD, director of Hepatology, and his colleague Fanyin Meng, PhD, also joined the Division in 2007. Patel is a member of The Ohio State University Comprehensive Cancer Center; his NIH-funded research program focuses on cellular mechanisms by which cytokines modulate cell survival and growth of cholangiocarcinoma. His laboratory also is investigating the role of miR-21 expression in human hepatocellular cancer. QiQi Zhou, MD, PhD, also joined the Division in 2007 and performs translational research evaluating mechanisms of central sensitization and hyperalgesia in humans and animal models of functional bowel disorders.

Ongoing Research Programs

The inflammation-associated cytokine interleukin-6 is implicated in the pathogenesis of cancers such as cholangiocarcinoma. Studies led by Tushar Patel, MD, seek to identify
cellular mechanisms by which this cytokine modulates cell survival and growth and to reveal cellular targets for therapeutic intervention.
Tushar Patel, MD, examines the role of non-coding RNA in the pathogenesis of liver cancers and in developing effective therapeutic strategies for liver cancers.
The role of corticotrophin-releasing factor (CRF) in stressrelated colonic dysfunction is studied by Sumei Liu, PhD. Her work focuses on CRF and its receptors’ expression in the
colonic myenteric and submucosal plexus.
Sumei Liu, PhD, studies transducin repeat-containing protein (TRCP) channels in intestinal secretion. This research focuses on intracellular signal transduction mechanisms that lead to activation of native TRPC channels in intestinal submucosal secretomotor neurons.
G. Nicholas Verne, MD, and QiQi Zhou, MD, PhD, are studying mechanisms of visceral pain in patients with functional bowel disorders at OSUMC and in veterans at the Department of Veteran Affairs outpatient clinic in Columbus, Ohio.

Research Accomplishments of 2007

Tushar Patel, MD, defined a mechanism by which inflammation-associated cytokines can epigenetically modulate gene expression, and he identified a relationship between interleukin-6 and methylation-dependent regulation of micro-RNAs involved in tumor-cell proliferation. He also identified involvement of miR-370 in cholangiocarcinoma growth.
Tushar Patel, MD, showed that miR-21 expression is increased in human hepatocellular cancer and that miR-21 promotes cell invasion, migration and growth.
Tushar Patel, MD, identified repression of PTEN gene expression and downstream effector kinases as a mechanism by which miR-21 affects HCC growth. Patel also examined
differences in response of endothelial cells to chemotherapy in experimental liver cancer. Studies revealed that the involvement of Akt genes in nuclear factor-kappa B (NFkB)-
dependent angiogenesis differed in tumor-derived and non-tumor-derived endothelial cells.
Sumei Liu, PhD, completed the characterization of chronic renal failure (CRF) and receptors expression in the colonic enteric nervous system.
Sumei Liu, PhD, generated a site-specific (colon) CRF “knockdown” animal model by double-stranded RNA-mediated RNA interference and used it to investigate the role of
peripheral CRF in stress-induced colon dysfunction.
QiQi Zhou, MD, PhD, developed an animal model of visceral and somatic hypersensitivity that has characteristics of central sensitization.
QiQi Zhou, MD, PhD, showed that upregulation of the Nmethyl d-aspartate (NMDA) receptor modulates persistent hypersensitivity in trinitrobenzene sulfonic acid (TNBS)-
induced colitis.

Division of General Internal Medicine
Catherine Lucey, MD, Director
General Internal Medicine provides comprehensive patient care to an increasingly complex community of patients while educating the next generation of physicians. Division members have achieved local and national recognition for patient care, teaching and educational leadership. They also are involved in numerous research projects. The Division is strongly focused on medical education, and its faculty are educational leaders in department and college activities. Catherine Lucey, MD, stepped down as residency program director to become vice dean for education in the College of Medicine. Cynthia Ledford, MD, serves as director of student education in the Department of Internal Medicine and as the third-year clerkship director. Robert Murden, MD, is associate director of admissions for the College of Medicine. Division physicians have authored multiple book chapters on topics ranging from physical diagnosis and clinical decisionmaking to perioperative issues and the educational approach to dealing with problem residents.

Ongoing Research Programs and Accomplishments of 2007

The Division recruited health-services researcher Deborah Levine, MD, MPH, whose work centers on the impact of race, ethnicity, insurance and physician factors on secondary prevention for stroke survivors.
Cynthia Ledford, MD, continued her Health Resources and Services Administration (HRSA)-funded grant on communitybased faculty development for student preceptors and submitted a follow-up grant to provide faculty development for resident preceptors.
Catherine Lucey, MD, led the Accreditation Council for Graduate Medical Education’s (ACGME) “Educational Innovations Project: Impact of Residency Education on
Patient Outcomes.” Areas of involvement include: a coordinated approach to education about and management of ambulatory patients with chronic pain syndromes; introduction
of quality improvement into the Internal Medicine resident clinic; and improving access by altering educational paradigms
– the impact of block group practice rather than weekly continuity practice on access, continuity and satisfaction.
In collaboration with the College of Medicine and the National Board of Medical Examiners, the Division is evaluating the effectiveness of faculty development in assessing professionalism among residents.
Catherine Lucey, MD, and Mitchell Medow, MD, were co-investigators for a National Institutes of Health (NIH) T32 training grant led by Philip Binkley, MD, of the Division of
Cardiovascular Medicine. The goal of this predoctoral training program is to increase the number of health professionals with formal education in clinical investigation.
Cynthia Kreger, MD, is a co-investigator on the predoctoral training in primary care (“Teaching to the CORE”) grant funded by the HRSA and led by Doug Knutson, MD.
Andrew Thomas, MD, is co-investigator for a National Cancer Institute (NCI)-grant titled “Enhancing Colorectal Cancer Screening in Primary Care” and an American Cancer
Society grant for the Ohio Patient Navigation Program, both led by Electra Paskett, PhD, MSPH.
In collaboration with the College of Medicine and the Department of Family Medicine, members of the Division submitted two HRSA grant proposals in December. One focuses on establishing an academic administrative unit to enhance the care of patients with chronic disease; the other focuses on a curriculum revision to support care of patients
with chronic disease.

Division of Hematology and Oncology
John Byrd, MD, Interim Co-Director
Gregory Otterson, MD, Interim Co-Director
Researchers in Hematology and Oncology develop drug therapies for treating solid tumor
and hematologic malignancies while focusing on cancer prevention through nutrition and
natural products. 2007 saw the continuation of several longstanding grants worth millions of dollars for members of this Division, as well as new endeavors to support the training of
additional physician-scientists in experimental therapeutics. The Division is enhancing training opportunities for fellows and junior faculty wanting to do clinical research in this discipline. Division members have submitted T32 and K12 grant applications to support such endeavors; these are undergoing peer review. Continued strategic development of supportive infrastructure to recruit outstanding junior- and mid-level physician scientists to Hematology and Oncology remains a top priority.

Ongoing Research Programs

Guido Marcucci, MD, William Blum, MD, Steven Devine, MD, and Clara D. Bloomfield, MD, are leading a grantfunded project to study biomarkers that predict outcome in acute myeloid leukemia and strategies to target these biomarkers with therapeutic agents. This effort has identified novel miR signatures associated with adverse outcome and also validated epigenetic modifications as an important feature in how hypomethylating agents work.
Multimillion-dollar grants from the National Cancer Institute (NCI) for phase I and phase II clinical trials of anticancer agents are helping investigators develop drugs for treating solid and hematologic tumors in pharmacokinetic and pharmacodynamic studies. Michael Grever, MD, is principal investigator (PI) for the longstanding phase I grant, which in 2007 was renewed for five years through the efforts of Grever, John Byrd, MD, James Thomas, MD, PhD, Andrea Inman and Fred Cope, PhD. Miguel Villalona, MD, is PI for the phase II grant. This program also fosters the study of agents on researcher-initiated investigational drugs or industrysponsored studies led by Ohio State investigators.
A major study of chronic lymphocytic leukemia (CLL) biology and therapeutics is supported by a five-year, $6.25 million specialized center of research (SCOR) grant from the Leukemia & Lymphoma Society (PI: John Byrd, MD), a P01 grant from the NCI (PI: Samson Jacob, MD), and several smaller grants. This project is directed by Byrd and
Thomas Lin, MD, PhD.
A Cancer Survivorship Center funded by a $1.25 million grant from the Lance Armstrong Foundation supports patients with long-term complications or other issues that arise after
completion of therapy for cancer. Charles Shapiro, MD, directs the Center; Electra Paskett, PhD, MSPH, is co-director.
Further studies of the human immune system’s innate ability to battle cancer are supported by a $10 million renewal of an NCI program project grant originally awarded in 2002 for $9.5 million. This study, led by Michael Caligiuri, MD, seeks to develop immune-based therapies for solid tumors and hematologic malignancies. Other leaders in this effort are John Byrd, MD, William Carson II , MD, Natarajan Muthusamy, DVM, PhD, Susheela Tridandapani, PhD, Robert Baiocchi, MD, PhD, Tanio Bekaii-Saab, MD, David Jarjoura, PhD, and Fred Cope, PhD.
Research is ongoing through foundation grants awarded to junior faculty members Don Benson, MD, PhD, Leslie Andritsos, MD, and Craig Hofmeister, MD. Research Accomplishments of 2007
Charles Shapiro, MD, published a highly noticed paper on sexual well-being among partnered women with breast cancer recurrence.
William Blum, MD, and Guido Marcucci, MD, published the first true validation that hypomethylating agents are actually working via this pathway to produce responses in AML.
Gregory Otterson, MD, published the first phase I study on 2008 Research Report 65
inhalational chemotherapy in cancer patients. This work will proceed to phase II validation studies.
Thomas Lin, MD, PhD, John Byrd, MD, Michael Grever, MD, and others published a phase I study demonstrating dramatic activity of flavopiridol in CLL. This agent has entered formal phase III testing.
Michael Caligiuri, MD, published a sentinel paper on natural killer (NK) cell development.

Division of Human Genetics
Albert de la Chapelle, MD, PhD, Interim Director

Human Genetics (HG) is a platform for translational and clinical research, clinical activities, education and outreach. The Division augments OSUMC’s leadership in gene discovery/characterization and molecular epidemiology while setting
standards for the clinical management of patients with genetic predisposition, and setting societal guidelines for the research and clinical use of genetic information. HG clinical activities provide genetic counseling to patients and families, and expert consultations to physicians and other professionals. HG provides adult medical genetics care to residents of central Ohio and surrounding states, and gives patients and physicians free access to HG research protocols. The Division coordinates clinical-genomic databases, specimen
repositories and the use of both in-house and referral diagnostic facilities to support clinical research in human genetics. HG staff enrolled 2,050 patients on non-therapeutic clinical trials in 2007, mainly studies initiated by OSUMC investigators.

Ongoing Research Programs

The “Genetic Modifiers of Breast and Ovarian Cancer Risk” study is part of an international Consortium of Investigators of Modifiers of BrcA1/2 (CIMBA). Amanda Toland, PhD, is
principal investigator (PI), and Kevin Sweet, MS, CGC, is study coordinator. CIMBA will accrue more than 20,000 people worldwide with known deleterious BRCA mutations in
an effort to: identify genetic modifiers of breast and ovarian cancer risk; identify additional high-penetrance genetic risk factors for familial breast/ovarian cancer; and correlate these
findings with low-penetrance risk factors affecting cancer risk in the general population. In 2007, 61 patients were accrued to this study.
The “Familial Papillary Thyroid Cancer (PTC)” study searches for genes that predispose to PTC. Albert de la Chapelle, MD, PhD, is PI, and Rebecca Nagy, MS, CGC, is study coordinator. In 2007, 126 patients were accrued.
The “PTEN Breast Cancer Bank,” initiated as a study to determine the incidence of germline PTEN mutations in a population-based series of incident breast cancers, has been replaced by the “Breast-Banking Protocol” with Charles Shapiro, MD, as PI and Robert Pilarski, MS, CGC, as coordinator. The breast bank is available to Ohio State researchers on a fee-per-sample basis and includes: germline DNA, RNA and lymphoblastoid cell lines; tumor DNA and RNA; normal adjacent tissue DNA and RNA; and tissue microarray slides. In 2007, 314 patients who received genetic testing for
germline PTEN mutations were accrued to these studies; total accrual at the end of the year was 1,215.
The “Controls for Genetics Research” study has Albert de la Chapelle, MD, PhD, as PI and Amy Sturm, MS, CGC, as coordinator. The primary objective is to create a bank of
control samples for use as a general resource for researchers in human genetics by collecting and storing clinical and family history information along with blood samples. In 2007, 491 patients were accrued; total accrual at the end of the
year was 577.

Research Accomplishments of 2007

Albert de la Chapelle, MD, PhD, along with researchers in Ohio State’s Human Cancer Genetics Program and clinicians from the Division of Hematology and Oncology, published a major paper in the journal Cell on “Downregulation of Death-Associated Protein Kinase 1 (DAPK1) in Chronic Lymphocytic Leukemia.” They discovered that the cause of inherited CLL in one large family is a germline mutation in the DAPK1 gene. This work has led to further studies involving DAPK1 with R01 and SPOR grant submissions being planned. Leigha Senter, MS, CGC, coordinates the CLL study, and Ilene Comeras, RN, OCN, is the study nurse.
The Columbus-area “Hereditary Non-Polyposis Colorectal Cancer” (HNPCC) study led by Albert de la Chapelle, MD, PhD, and coordinated by Heather Hampel, MS, CGC, resulted
in four publications in 2007 and has led to numerous spin-off studies, including a PMS2 study, an American founder mutation study and a gene-hunting study involving MSI-negative colorectal cancer. Publications in 2007 included: “Evidence for Heritable Predisposition to Epigenetic Silencing of MLH1” (International Journal of Cancer); “Multifocal Anaplastic Astrocytoma in a Patient with Hereditary Colorectal Cancer,
Transcobalamin II Deficiency, Agenesis of the Corpus Callosum, Mental Retardation, and Inherited PMS2 Mutation” (Neurological Oncology); “Comment on Screening for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) among Endometrial Cancer Patients” (Cancer Research); and “Correlation Between Patient Weight and Defects in DNA Mismatch Repair: Is This the Link Between an Increased Risk of Previous Cancer in Thinner Women with Endometrial Cancer?” (International Journal of Gynecologic Cancer). At least three additional manuscripts are in press, under review or in preparation as a result of this study.

Division of Immunology
Ronald Whisler, MD, Director
This Division makes advances in academic excellence and research while also serving the University and the community in the clinical setting. The Division’s publications and peer-reviewed grants demonstrate considerable strength. For example, Clark Anderson, MD, is
furthering his National Institutes of Health (NIH)-supported studies of Fc receptors, while Kevin Hackshaw, MD, and Ronald Whisler, MD, serve as co-principal investigators with Rebecca Jackson, MD, on the Osteoarthritis Initiative funded by the NIH. Division members have been conducting clinical investigations into more efficacious treatment regimens for rheumatoid arthritis, systemic lupus erythematosus, fibromyalgia, osteoporosis and osteoarthritis.

Ongoing Research Programs and Accomplishments of 2007

Clark Anderson, MD, leads a study titled “FcRn Binds and Transports Albumin.”
Kevin Hackshaw, MD, and Ronald Whisler, MD, lead a study titled “Clinical Centers for the Osteoarthritis Initiative.”
Kevin Hackshaw, MD, is site principal investigator (PI) for “Phase III Randomized Double-Blind Placebo-Controlled Multicenter Study of Retreatment with Rituximab in Subjects
With Rheumatoid Arthritis who are Receiving Background Methotrexate.”
Ronald Whisler, MD, and Kevin Hackshaw, MD, are site PIs for “A Randomized Phase III Controlled Double-Blind Parallel-Group Multicenter Study to Evaluate the Safety and
Efficacy of Rituximab in Combination with Methotrexate (MTX) Compared to MTX Alone in Methotrexate-Naive Patients with Active Rheumatoid Arthritis.”

Division of Infectious Diseases
Larry Schlesinger, MD, Director
Infectious Diseases continued its commitment to research by submitting 22 grants in 2007. Its annual research budget has grown from approximately $1.5 million in 2002 to more than $4 million. Research awards include $13.59 million from the National Institutes of Health (NIH), Health Resources and Services Administration (HRSA), and Department of Health and Human Services (DHHS) to support studies for patients with HIV/AIDS, including the HRSA AIDS Education and Training Center. The NIH-awarded AIDS Clinical Trials Unit (ACTU) at Ohio State ranks highly among research awards across the University. Research awards for Division faculty who are also core members of Ohio State’s Center for Microbial Interface Biology (CMIB) totaled $9.83 million, including a new NIH training grant in infectious diseases/microbial pathogenesis. The Division also participates in the nearly $5 million Targeted Investment in Excellence Award Program from the Office of Academic Affairs in Public Health Preparedness for Infectious Diseases.

Ongoing Research Programs

Adult AIDS Clinical Trials Unit (ACTU) – Led by Susan Koletar, MD, the ACTU at Ohio State is part of a multicenter group that conducts clinical trials research to increase knowledge about the pathogenesis, prevention, course and treatment of HIV infection and associated complications.
The national Centers for Disease Control has designated Ohio State as one of five (nationally) Epi-Centers for Prevention of Healthcare Related Infections. This Ohio State Health Network Infection Control Collaborative comprises the University and 14 outreach sites that improve surveillance for healthcare-associated infections, antimicrobial resistance and other adverse events by optimizing electronic healthinformation systems. The total award for this five-year project, which is led at Ohio State by Kurt Stevenson, MD, MPH, is $1.97 million.
Great Lakes Regional Center of Excellence (RCE) in Biodefense and Emerging Infectious Disease Research - Led by Larry Schlesinger, MD, this program grant, entitled “Lung Innate Immune Responses to Francisella tularensis: A Central Role for the Macrophage” includes investigators in the CMIB and at Ohio State’s Davis Heart and Lung Research
Institute who explore lung immune responses to these bacteria – especially as they relate to interactions with macrophages – to identify molecular targets for new diagnostic strategies as well as targeted immune therapies to enhance host immunity.
Joanne Turner, PhD, directs a study titled “CD8 T Cells and Immunity to Tuberculosis in Old Mice.” Funded by the National Institute of Allergy and Infectious Diseases, this study seeks to understand how the aging immune system response differs from that of younger individuals when it encounters a pathogen. The goal is to design a vaccine or postexposure therapy that can protect the elderly against infectious disease.
Led by Julie Mangino, MD, a multicenter performanceimprovement project titled “Improving Medicine Through Pathway Assessment of Clinical Therapy in Hospital-Acquired Pneumonia” aims to optimize management of healthcare-associated pneumonia, hospital-acquired pneumonia and ventilator-associated pneumonia in the Medical Center’s ICU and the University Hospital East ICU via compliance with national guidelines of the American Thoracic Society/Infectious Disease Society of America. The schema is to perform a clinical and microbiologic workup with initiation of broad- spectrum antibiotics followed by a de-escalation/discontinuation of these agents based on clinical and microbiologic data.

Research Accomplishments of 2007

The ACTU continued advancing AIDS care by conducting clinical research that increases knowledge about the pathogenesis, prevention, course and treatment of HIV infection and its associated complications through affiliation with the national and international organization, the AIDS Clinical Trials Group (ACTG). Ohio State’s ACTU has been refunded through 2013 with a total award of $11.9 million.
A campuswide OSU Provost Targeted Investment in Excellence program entitled “Public Health Preparedness for Infectious Diseases (PHPID)” is enhancing public health by
minimizing animal-to-human, environmental and food-borne infectious disease threats through interdisciplinary research. PHPID was founded as a collaboration among six Ohio State colleges (Medicine, Public Health, Veterinary Medicine, Food/Agricultural and Environmental Sciences, Pharmacy, and Biological Sciences) with the goal of providing leadership in scientific discoveries and training of health professionals to prevent or mitigate the public-health impact of catastrophic events. PHPID provides stipends for graduate education and pilot research funds for collaborative science; the total award is $4.7 million, with $979,068 awarded to the College of Medicine/Division of Infectious Diseases.
With support from the CMIB, Larry Schlesinger, MD, became principal investigator of a $674,045, five-year NIH T32 training grant titled “Interdisciplinary Study of the Microbe-Host Interface.” This grant supports two predoctoral trainees and one postdoctoral trainee per year in microbial and host response to infection. The training program includes faculty from seven departments (four basic sciences and three clinical) and three PhD, MD, MD/
PhD, and DVM degree-granting programs.
Jesse Kwiek, PhD, a newly recruited faculty member, received the coveted NIH K99/R00 early-career award for a study titled “Viral and Placental Determinants of HIV-1 Subtype C Mother-to-Child Transmission.” This study will determine viral genotypes and/or phenotypes associated with in utero HIV-1 mother-to-child transmission, and whether placental receptors and co-receptors (CD4/CCR5/CXCR4) are associated with in utero HIV-1 mother-to-child transmission. The total award is $497,277.

Division of Nephrology
Brad Rovin, MD, Director
Nephrology provides care for patients with chronic kidney disease, acute kidney injury, hypertension, glomerulonephritis, electrolyte and acid-base disorders, and solid organ transplants. The Division has been ranked in the top 25 Nephrology Divisions in the country by U.S.News & World Report for the past several years; four faculty members were recognized as Best Doctors in America in 2007. Besides clinical care, Nephrology is engaged in basic science, translational and clinical research to define mechanisms of kidney disease, identify therapeutic targets for treating it, and test novel therapies for kidney problems. The Division is recognized internationally for its work in systemic lupus erythematosus (SLE), urine biomarker discovery, anemia of chronic kidney disease, and calcium-phosphate homeostasis in kidney failure. Research is supported by grants from the National Institutes
of Health (NIH), private foundations and the pharmaceutical industry.

Ongoing Research Programs

The Human Glomerulonephritis program characterizes clinical, genetic, environmental and novel biochemical risk factors for glomerular diseases. The primary focus has been the glomerulonephritis of systemic lupus erythematosus, although other glomerulopathies are also studied.
In the Urine Biomarker Discovery program, investigators have developed expertise in proteomics and mass spectroscopy to identify urine biomarkers that may be used to predict the onset, severity and prognosis of glomerular diseases.
The NIH-sponsored “African-American Study of Kidney Disease and Hypertension” is a clinical trial examining risk factors for kidney disease and hypertension in African-
Americans.
Through the Lupus Clinical Trials Consortium, the Division participates in multicenter international trials of new therapeutics for lupus nephritis.
The Nephrology Clinical Trials Unit is involved in studies to define best-management approaches to anemia, phosphate balance and hyperparathyroidism in chronic kidney disease.
The Division of Nephrology and Ohio State’s Comprehensive Transplant Center are participating in several prospective ongoing clinical trials in transplantation and are the largest enrolling centers:
– Uday Nori, MD, is principal investigator (PI) for a multicenter phase III trial titled “A Randomized, Open-Label, Multicenter, Parallel-Group Study of Belatacept-Based,
Corticosteroid-Free Regimens in Renal Transplant.” This is a novel approach to preventing acute rejection with broad implications for the treatment of immunologic diseases.
– A placebo-controlled prospective trial is studying whether
homocysteine reduction will result in a decline of cardiovascular
events in kidney-transplant patients.
– Todd Pesavento, MD, is site PI for a multicenter NIH trial studying the long-term outcome of living kidney donors and assessing the effect of diminished renal function on
cardiovascular outcomes. This trial will have broad application to patients with renal disease and will help ensure the long-term health of live renal donors.

Research Accomplishments of 2007

Using SELDI-TOF mass spectroscopy, Brad Rovin, MD, and Xiaolan Zhang, MD, discovered that the small peptide hormone hepcidin is differentially expressed in the urine of patients undergoing lupus nephritis flares. Urine hepcidin may therefore be a biomarker that can be used to predict impending SLE renal flare. Rovin and Zhang have received a
provisional patent on hepcidin for this use and are developing more quantitative assays for measuring urine hepcidin to verify the SELDI-TOF data.
Brad Rovin, MD, working with Nephrology fellow Daniel Roncone, DO, and MPH student Alison McKinley, identified a mutation in the apolipoprotein E gene that is necessary for
the development of lipoprotein glomerulopathy in European-Americans. This study also showed that the mutation is not sufficient for disease development and requires a second
event for full disease expression. This second event is being investigated.
The urine dipstick is frequently used in the diagnosis of SLE renal flares, but its accuracy has been questioned. Working with investigators at Johns Hopkins, the laboratory of Brad
Rovin, MD, showed that urine dipstick protein measurements are not adequate to screen for changes in proteinuria that may be diagnostic of renal lupus activation. This work should change the way lupus nephritis flares are approached diagnostically.
Lee Hebert, MD, and Daniel Birmingham, PhD, assessed the reliability of spot urine protein/creatinine ratios (P/C) to assess 24-hour proteinuria in the Ohio SLE Study cohort. This is an important issue in clinical lupus nephritis treatment, as 24-hour proteinuria is the gold standard for assessing kidney function, and the National Kidney Foundation Kidney Disease Outcomes Quality Initiative has approved the use of spot urine P/C for assessing 24-hour proteinuria. The Ohio State study found that spot urines do not reliably estimate 24-hour proteinuria in the range of most lupus nephritis flares.
Daniel Birmingham, PhD, discovered a polymorphism in one of the ligand-binding domains of the type 1 complement receptor (CR1), an immune complex receptor and complement regulator that contributes to protection from SLE. The variant form, present with an allele frequency of 6 percent in blacks and 2 percent in whites, abolishes the domain’s ligand-binding capacity. Evidence suggests that, though not a risk factor for SLE or lupus nephritis by itself, the variant form does contribute risk when occurring on CR1 allotypes expressing relatively low numbers of binding domains.
Collaborations with other investigators studying human SLE and other autoimmune diseases have led to the identification of additional risk factors for SLE and/or lupus nephritis, including gene copy number variation in the C4 gene, a promoter polymorphism in the type 2 complement receptor (CR2) that affects transcription levels, and a polymorphism in the 5’ region of CD24, a marker associated with T-cell expansion that affects transcript levels.
Anil Agarwal, MD, has helped establish a new paradigm of extended dosing of erythropoiesis-stimulating agent Darbepoetin for elderly patients.

Division of Pulmonary, Allergy, Critical Care and Sleep Medicine
Clay Marsh, MD, Director

This Division focuses on clinical medicine, translational research and education. Seventeen of 19 physicians in America’s Best Doctors in pulmonary and critical care medicine from central Ohio are in this Division. Its ICU and pulmonary care are rated outstanding by Healthgrades™.
Investigators are collaborating with Johns Hopkins University in a trial of high-frequency oscillating ventilators in acute respiratory distress syndrome (ARDS), and they are creating a
registry of patients with life-threatening infections. The Division has National Institutes of Health support for studying effects of long-term oxygen therapy in emphysema and for translational research in asthma, pulmonary fibrosis, lung cancer, lung complications of bone marrow transplantation, and infectious disease in the lung. It partners with the Institute for Behavioral Medicine Research to understand the role of chronic stress in advanced lung disease. After recruiting Bryan Martin, MD, as director of allergy, the Division has the first fellowship program in Allergy/Immunology at Ohio State. In sleep medicine, investigators
study the role of sleep-disordered breathing in heart failure and the role of adipokines and intermittent hypoxemia in glucose intolerance.

Ongoing Research Programs

Funded by the National Heart, Lung and Blood Institute (NHLBI) and led at Ohio State by Philip Diaz, MD, the “Long-Term Oxygen Treatment Trial” is a multisite study to determine
health effects of long-term supplemental oxygen therapy on patients with hypoxemia and advanced emphysema.
Led by John Mastronarde, MD, and funded by the NHLBI and the American Lung Association, the “Asthma Clinical Research Network” is a multisite study testing practical
issues in treating and managing asthma.
The “MicroRNA and Systems Biology in Human Lung and Critical Care Disease” study, funded by Battelle Industries and the CHEST Foundation, is led by Clay Marsh, MD,
Patrick Nana-Sinkam, MD, and Melissa Hunter, PhD. It seeks to define gene pathway perturbations and effects on microRNAs in advanced lung disease and critical care disease to identify biosignatures for disease prediction, treatment outcome and progression. The program integrates OSUMC, Ohio State’s Mathematical Biosciences Institute, Information Warehouse, and Center for Biostatistics, and it partners with
Battelle Industries and the Institute for Systems Biology in Seattle.
The “High-Frequency Oscillating Ventilation in ARDS” study, funded by Johns Hopkins University and the NHLBI, is led by Scott Aberegg, MD, MPH, James O’Brien, MD, and
Naeem Ali, MD. It is evaluating the utility and safety of highfrequency oscillating ventilation (HFOV) for treating ARDS. Previous work from ARDSnet suggests that lowered tidal
volume ventilation is protective in ARDS, and HFOV gives the lowest tidal volumes to patients.
The “Sepsis Registry and Biomarkers in Sepsis” study, funded by the NHLBI and led by Naeem Ali, MD, Mark Wewers, MD, and James O’Brien, MD, is identifying clinical, laboratory and genetic signatures that will allow scientists to predict outcomes and response to treatment, and to identify molecular targets for patients with sepsis.
The “Behavioral Stress and Microenvironment in Advanced Lung Disease” study, funded by the National Cancer Institute and the NHLBI, is led by Clay Marsh, MD, Philip Diaz, MD, Ronald Glaser, PhD, John Sheridan, PhD, Charles Emory, PhD, and Michael Ostrowski, PhD. It is testing the hypothesis that chronic stress and depression drive outcomes in patients with advanced lung disease. Scientists are investigating outcomes and comparing stress/depression inventories with network analysis and evaluation of the lung microenvironment in these patients and in animal models of advanced lung disease.
The “Innate Immunity and Host Defense in Lung Disease” study, funded by the National Institute of Allergy and Infectious Diseases (NIAID), is led by Mark Wewers, MD, Susheela Tridandapani, PhD, Larry Schlesinger, MD, John Gunn, PhD, and Amal Amer, PhD. This study examines the impact of the innate immune system in outcomes from
infection with Tularemia species using cell and animal models and materials from patients. In addition, the “Lung Inflammation and Experimental Therapeutics” study is led by Andrea Doseff, PhD, Daren Knoell, PharmD, Matt Exline, MD, Elliott Crouser, MD, and Beth Besecker, MD, who are exploring how cellular survival and homeostasis influence
host outcome after lung surgery.
The “Lung Emphysema Treatment Trial” led by Phillip Diaz, MD, found that patients with advanced emphysema who did not have symptom resolution with rehabilitation and functional lung did better with lung-volume-reduction surgery than with medical treatment.
The “Weakness and ICU Readmission Evaluation (WIRE)” study, led by Naeem Ali, MD, found that patients with objective weakness had significantly increased risk of death compared with patients with normal strength, RR 4.7.
The Division launched the “Innate Immune System Program in Human Disease,” which is supported by the NHLBI, the NIAID and Ohio State’s Davis Heart and Lung Research
Institute. Led by Mark Wewers, MD, Susheela Tridandapani, PhD, Andrea Doseff, PhD, and Clay Marsh, MD, this study focuses on strengths in macrophage biology and the role of the innate immune system in cancer, lung-injury repair and remodeling, and host response in infectious disease.
The “Epithelial Cell Function and Survival” study, funded by the NHLBI and led by Daren Knoell, PhD, is identifying zinc-dependent transporters and other genetic factors that have powerful effects on cellular survival and activation in epithelial cells.
The “Clinical Research Program in Critical Care,” funded by the NHLBI and led by James O’Brien, MD, Naeem Ali, MD, and Scott Aberegg, MD, MPH, focuses on clinical research
areas in sepsis and medical decision making.
The “Asthma Clinical Research Program,” funded by the NHLBI and the ALA and led by John Mastronarde, MD, and Jonathan Parsons, MD, examines clinical research issues in
asthma with an emphasis on asthma and athletes.